2EASL_HBV_CPGs
EASL Clinical Practice Guidelines:Management of chronic hepatitis B
European Association for the Study of the Liver *
Keywords :Hepatitis B virus;EASL guidelines;Treatment;Interferon alpha;Nucleoside/nucleotide analogues
1.Introduction
Our understanding of the natural history of hepatitis B virus (HBV)infection and the potential for therapy of the resultant disease has improved.Several new and e?ective antiviral agents have been evaluated and licensed since the EASL International Consensus Conference on hepatitis B held in 2002[1].The objective of these EASL Clinical Practice Guidelines (CPGs)is to update recommenda-tions for the optimal management of chronic hepatitis B (CHB).The CPGs do not focus on prevention and vacci-nation.Several di?culties remain in formulating treat-ments for CHB;thus areas of uncertainty exist.At the present time clinicians,patients and public health author-ities must continue to make choices on the basis of evi-dence that is not fully matured.2.Context
2.1.Epidemiology and public health burden
Approximately one third of the world’s population has serological evidence of past or present infection with HBV and 350million people are chronically infected.The spectrum of disease and natural history of chronic HBV infection is diverse and variable,ranging from a low viremic inactive carrier state to progressive chronic hepatitis,which may evolve to cirrhosis and hepatocellu-lar carcinoma (HCC).HBV-related end stage liver dis-
ease or HCC are responsible for over 1million deaths per year and currently represent 5–10%of cases of liver transplantation [2–5].Host and viral factors,as well as coinfection with other viruses,in particular hepatitis C virus (HCV),hepatitis D virus (HDV),or human immu-node?ciency viru s (HIV)together with other co-mor-bidities including alcohol abuse and overweight,can a?ect the natural course of HBV infection as well as the e?cacy of antiviral strategies.
CHB may present either as hepatitis B e antigen (HBeAg)-positive or HBeAg-negative CHB.HBeAg-positive CHB is due to so-called ‘‘wild type ”HBV.It typically represents the early phase of chronic HBV infection.HBeAg-negative CHB is due to replication of naturally occurring HBV variants with nucleotide substitutions in the precore and/or basic core promoter regions of the genome and represents a later phase of chronic HBV infection.The prevalence of the HBeAg-negative form of the disease has been increasing over the last decade as a result of HBV-infected population aging and represents the majority of cases in many areas,including Europe [6–8].
Morbidity and mortality in CHB are linked to persis-tence of viral replication and evolution to cirrhosis or HCC.Longitudinal studies of patients with CHB indi-cate that,after diagnosis,the 5-year cumulative inci-dence of developing cirrhosis ranges from 8to 20%.The 5-year cumulative incidence of hepatic decompensa-tion is approximately 20%with the 5-year probability of
0168-8278/$34.00ó2008Published by Elsevier B.V.on behalf of the European Association for the Study of the Liver.doi:10.1016/j.jhep.2008.10.001
*
EASL o?ce,7rue des Battoirs,CH 1205Geneva,Switzerland.Tel.:+41228070360;fax:+41223280724.E-mail address:easlo?ce@easlo?ce.eu
Contributors:Clinical Practice Guidelines Panel:Patrick Marcellin,Geo?rey Dusheiko,Fabien Zoulim,Rafael Esteban,Stefanos Hadzi-yannis,Pietro Lampertico,Michael Manns,Daniel Shouval,Cihan Yurdaydin;Reviewers:Antonio Craxi,Xavier Forns,Darius Morad-pour,Jean-Michel Pawlotsky,Joerg Petersen,Heiner Wedemeyer.
https://www.360docs.net/doc/159186665.html,/locate/jhep
survival being approximately80–86%in patients with compensated cirrhosis[4,9–13].Patients with decompen-sated cirrhosis have a poor prognosis with a14–35% probability of survival at5years.The worldwide inci-dence of HCC has increased,mostly due to HBV and HCV infections;presently it constitutes the?fth most common cancer,representing around5%of all cancers. The annual incidence of HBV-related HCC in patients with CHB is high,ranging from2%to5%when cirrho-sis is established[13].However,the incidence of HBV-related HCC appears to vary geographically and corre-lates with the underlying stage of liver disease.
Population movements and migration are currently changing the prevalence and incidence of the disease in several low endemicity countries in Europe and else-where.Substantial healthcare resources will be required for control of the worldwide burden of disease.
2.2.Natural history
Chronic hepatitis B is a dynamic process.The natural history of CHB can be schematically divided into?ve phases,which are not necessarily sequential.
(1)The‘‘immune tolerant”phase is characterized by
HBeAg positivity,high levels of HBV replication
(re?ected by high levels of serum HBV DNA),nor-
mal or low levels of aminotransferases,mild or no
liver necroin?ammation and no or slow progres-
sion of?brosis[3,5].During this phase,the rate
of spontaneous HBeAg loss is very low.This?rst
phase is more frequent and more prolonged in sub-
jects infected perinatally or in the?rst years of life.
Because of high levels of viremia,these patients are
highly contagious.
(2)The‘‘immune reactive phase”is characterized by
HBeAg positivity,a lower level of replication(as
re?ected by lower serum HBV DNA levels),
increased or?uctuating levels of aminotransfer-
ases,moderate or severe liver necroin?ammation
and more rapid progression of?brosis compared
to the previous phase[3,5].It may last for several
weeks to several years.In addition,the rate of
spontaneous HBeAg loss is enhanced.This phase
may occur after several years of immune tolerance
and is more frequently reached in subjects infected
during adulthood.
(3)The‘‘inactive HBV carrier state”may follow sero-
conversion from HBeAg to anti-HBe antibodies.It
is characterized by very low or undetectable serum
HBV DNA levels and normal aminotransferases.
As a result of immunological control of the infec-
tion,this state confers a favourable long-term out-
come with a very low risk of cirrhosis or HCC in
the majority of patients.HBsAg loss and serocon-
version to anti-HBs antibodies may occur sponta-
neously in1–3%of cases per year,usually after
several years with persistently undetectable HBV
DNA[14].
(4)‘‘HBeAg-negative CHB”may follow seroconver-
sion from HBeAg to anti-HBe antibodies during
the immune reactive phase and represents a later
phase in the natural history of CHB.It is charac-
terized by periodic reactivation with a pattern of
?uctuating levels of HBV DNA and aminotrans-
ferases and active hepatitis.These patients are
HBeAg-negative,and harbour HBV variants with
nucleotide substitutions in the precore and/or the
basal core promoter regions unable to express or
expressing low levels of HBeAg.HBeAg-negative
CHB is associated with low rates of prolonged
spontaneous disease remission.It is important
and sometimes di?cult to distinguish true inactive
HBV carriers from patients with active HBeAg-
negative CHB in whom phases of spontaneous
remission may occur.The former patients have a
good prognosis with a very low risk of complica-
tions,while the latter patients have active liver dis-
ease with a high risk of progression to advanced
hepatic?brosis,cirrhosis and subsequent compli-
cations such as decompensated cirrhosis and
HCC.A careful assessment of the patient is needed
and a minimal follow-up of one year with serum
alanine aminotransferase(ALT)and HBV DNA
levels every3months usually allows detection of
?uctuations of activity in patients with active
HBeAg-negative CHB[15].
(5)In the‘‘HBsAg-negative phase”after HBsAg loss,
low-level HBV replication may persist with detect-
able HBV DNA in the liver[16].Generally,HBV
DNA is not detectable in the serum while anti-
HBc antibodies with or without anti-HBs are
detectable.HBsAg loss is associated with improve-
ment of the outcome with reduced risk of cirrhosis,
decompensation and HCC.The clinical relevance
of occult HBV infection(detectable HBV DNA
in the liver with low-level[<200international units
(IU)/ml]HBV DNA in blood)is unclear[16].
Immunosuppression may lead to reactivation in
these patients[17,18].
3.Methodology
These EASL CPGs have been developed by a CPG Panel of experts chosen by the EASL Governing Board; the recommendations were peer-reviewed by external expert reviewers and approved by the EASL Governing Board.The CPGs have been based as far as possible on evidence from existing publications,and,if evidence was unavailable,the experts’personal experience and opin-ion.Manuscripts and abstracts of important meetings
228European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
published prior to August2008have been evaluated. The evidence and recommendations in these guidelines have been graded according to the Grading of Recom-mendations Assessment Development and Evaluation (GRADE)system.The strength of recommendations thus re?ects the quality of underlying evidence.The principles of the GRADE system have been enunciated. The quality of the evidence in these CPGs has been clas-si?ed in one of three levels:high(A),moderate(B)or low(C).The GRADE system o?ers two grades of rec-ommendation:strong(1)or weak(2)(Table1).The CPGs thus consider the quality of evidence:the higher the quality of evidence,the more likely a strong recom-mendation is warranted;the greater the variability in values and preferences,or the greater the uncertainty, the more likely a weaker recommendation is warranted [19–25].
The CPG Panel members considered the following questions:
How should liver disease be assessed before therapy? What are the goals and end-points of treatment?
What are the de?nitions of response?
What is the optimal approach to?rst-line treatment? What are the predictors of response?
What de?nitions of resistance should be applied and how should resistance be managed?
How should treatment be monitored?
When can treatment be stopped?
How should special groups be treated?
What are the current unresolved issues?
4.Guidelines
4.1.Pretherapeutic assessment of liver disease
As a?rst step,the causal relationship between HBV infection and liver disease has to be established and an assessment of the severity of liver disease needs to be performed.Not all patients with CHB have persistently elevated aminotransferases.Patients in the immune tol-erant phase have persistently normal ALT levels and a proportion of patients with HBeAg-negative CHB may have intermittently normal ALT levels.Therefore appropriate,longitudinal long-term follow-up is crucial.
(1)The assessment of the severity of the liver disease
should include:biochemical markers,including
aspartate aminotransferase(AST)and ALT,
gamma-glutamyl transpeptidase(GGT),alkaline
phosphatase,prothrombin time and serum albu-
min;blood counts;and hepatic ultrasound(A1).
Usually,ALT levels are higher than those of AST.
However,when the disease progresses to cirrhosis,
the ratio may be reversed.A progressive decline in
serum albumin concentrations and prolongation
of the prothrombin time,often accompanied by a
drop in platelet counts,are characteristically
observed after cirrhosis has developed.
(2)HBV DNA detection and HBV DNA level mea-
surement is essential for the diagnosis,decision
to treat and subsequent monitoring of patients
(A1).Follow-up using real-time PCR quanti?ca-
tion assays is strongly recommended because of
their sensitivity,speci?city,accuracy and broad
dynamic range[26–29](A1).The World Health
Organization(WHO)has de?ned an international
standard for normalisation of expression of HBV
DNA concentrations[30].Serum HBV DNA lev-
els should be expressed in IU/ml to ensure compa-
rability;the same assay should be used in the same
patient to evaluate antiviral e?cacy(A1).
(3)Other causes of chronic liver disease should be sys-
tematically looked for including coinfection with
HDV,HCV and/or HIV.Co-morbidities,includ-
ing alcoholic,autoimmune,metabolic liver disease
with steatosis or steato-hepatitis should be
assessed(A1).
(4)A liver biopsy is recommended for determining the
degree of necroin?ammation and?brosis in patients
with either increased ALT or HBV DNA levels
>2000IU/ml(or both)since hepatic morphology
Table1
Grading of evidence and recommendations(adapted from the GRADE system)[19–25]
Notes Symbol Grading of evidence
High-quality evidence Further research is very unlikely to change our con?dence in the estimate of e?ect A Moderate-quality evidence Further research is likely to have an important impact on our con?dence in the estimate
of e?ect and may change the estimate
B
Low-or very low-quality evidence Further research is very likely to have an important impact on our con?dence in the
estimate of e?ect and is likely to change the estimate.Any estimate of e?ect is uncertain
C
Grading of recommendation
Strong recommendation warranted Factors in?uencing the strength of the recommendation included the quality of the
evidence,presumed patient-important outcomes,and cost
1
Weaker recommendation Variability in preferences and values,or more uncertainty:more likely a weak
recommendation is warranted.
2
Recommendation is made with less certainty;higher cost or resource consumption
European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242229
can assist the decision to start treatment(A1).
Biopsy is also useful for evaluating other possible
causes of liver disease such as steatosis or steato-
hepatitis.Although liver biopsy is an invasive proce-
dure,the risk of severe complications is very low(1/
4,000–10,000).It is important that the size of the
needle biopsy specimen be large enough to precisely
analyse the degree of liver injury and?brosis[31]
(A1).A liver biopsy is usually not required in
patients with clinical evidence of cirrhosis or in
those in whom treatment is indicated irrespective
of the grade of activity or the stage of?brosis
(A1).There is growing interest in the use of non-
invasive methods,including serum markers and
transient elastography,to assess hepatic?brosis to
complement or avoid a liver biopsy[32–36].
4.2.Goal of therapy
The goal of therapy for hepatitis B is to improve quality of life and survival by preventing progression of the disease to cirrhosis,decompensated cirrhosis, end-stage liver disease,HCC and death.This goal can be achieved if HBV replication can be suppressed in a sustained manner,the accompanying reduction in histo-logical activity of chronic hepatitis lessening the risk of cirrhosis and decreasing the risk of HCC in non-cir-rhotic patients and probably also,but to a lesser extent, in cirrhotic patients[37](B1).However,HBV infection cannot be completely eradicated due to the persistence of covalently closed circular DNA(cccDNA)in the nucleus of infected hepatocytes.
4.3.End-points of therapy
Therapy must reduce HBV DNA to as low a level as possible,ideally below the lower limit of detection of real-time PCR assays(10–15IU/ml),to ensure a degree of virological suppression that will then lead to biochemical remission,histological improvement and prevention of complications.Interferon alpha or nucle-oside/nucleotide analogue(NUC)therapy-induced HBV DNA reduction to low levels is associated with dis-ease remission.Sustained HBV DNA reduction to unde-tectable levels is necessary to reduce the risk of resistance to NUCs.It also increases the chance of HBe seroconversion in HBeAg-positive patients and the possibility of HBsAg loss on the mid to long term in HBeAg-positive and HBeAg-negative patients.If real-time PCR is unavailable,HBV DNA should be measured by the most sensitive assay possible.
(1)In HBeAg-positive and HBeAg-negative patients,
the ideal end-point of therapy is sustained HBsAg
loss with or without seroconversion to anti-HBs.
This is associated with a complete and de?nitive
remission of the activity of chronic hepatitis B
and an improved long-term outcome(A1).
(2)In HBeAg-positive patients,durable HBe serocon-
version is a satisfactory end-point because it has
been shown to be associated with improved prog-
nosis(A1).
(3)In HBeAg-positive patients who do not achieve
HBe seroconversion,and in HBeAg-negative
patients,a maintained undetectable HBV DNA
level on treatment with NUCs or a sustained unde-
tectable HBV DNA level after interferon therapy
is the next most desirable end-point(A1).
4.4.De?nitions of response
Two di?erent types of drugs can be used in the treatment of CHB:interferon alpha and nucleoside/ nucleotide analogues referred to collectively as NUCs in this document.The de?nition of response to antiviral therapy varies according to the type of therapy.
(1)On interferon alpha therapy:
Primary non-response is de?ned as less than1
log10IU/ml decrease in HBV DNA level from
baseline at3months of therapy.
Virological response is de?ned as an HBV DNA
concentration of less than2000IU/ml at24weeks
of therapy.
Serological response is de?ned by HBe serocon-
version in patients with HBeAg-positive CHB.
(2)On NUC therapy:
Primary non-response is de?ned as less than1
log10IU/ml decrease in HBV DNA level from
baseline at3months of therapy.
Virological response is de?ned as undetectable
HBV DNA by real-time PCR assay within48
of therapy.
virological response is de?ned as a decre-in HBV DNA of more than1log10IU/ml but detectable HBV DNA by real-time PCR assay.
A partial virological response should be assessed
to modify therapy at24weeks of treatment for
moderately potent drugs or drugs with a low
genetic barrier to resistance(lamivudine and
telbivudine)and at48weeks of treatment for
highly potent drugs,drugs with a higher genetic
barrier to resistance or drugs with a late
emergence of resistance(entecavir,adefovir and
tenofovir).
Virological breakthrough is de?ned as a
con?rmed increase in HBV DNA level of more
than1log10IU/ml compared to the nadir(low-
230European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
est value)HBV DNA level on therapy;it usu-ally precedes a biochemical breakthrough,characterized by an increase in ALT levels.The main causes of virological breakthrough on NUC therapy are poor adherence to therapy and selection of drug-resistant HBV variants (resistance)(A1).
HBV resistance to NUCs is characterized by selection of HBV variants with amino acid sub-stitutions that confer reduced susceptibility to the administered NUC(s).Resistance may result in primary treatment failure or virological breakthrough on therapy (A1).
4.5.Results of current therapies
Seven drugs are now available for the treatment of chronic hepatitis B:they include conventional interferon alpha,pegylated interferon alpha and NUCs.NUCs for HBV therapy belong to three classes:L-nucleosides (lamivudine,telbivudine,and emtricitabine),deoxygua-nosine analogues (entecavir)and acyclic nucleoside phosphonates (adefovir and tenofovir).Lamivudine,adefovir,entecavir,telbivudine and tenofovir have been approved in Europe for HBV treatment,and the combi-nation of tenofovir and emtricitabine in one tablet has been licensed for the treatment of HIV infection.
The e?cacy of these drugs has been assessed in ran-domized controlled trials at one year (two years with telbivudine).Longer-term results (up to 5years)are available for lamivudine,adefovir,entecavir,telbivu-dine and tenofovir in patient subgroups.Figs.1and 2show response rates with these drugs from di?erent trials.These trials used di?erent HBV DNA assays and they were not head-to-head comparisons for all the drugs.
(1)In HBeAg-positive patients,virological response
rates at one year (undetectable HBV DNA,de?ned variously in the di?erent trials and di?erently from the present guidelines)were 25%,36–40%,21%,67%,60%and 74%with pegylated interferon alpha-2a/2b,lamivudine,adefovir,entecavir,telbivudine and tenofovir,respectively (Fig.1)[38–44].HBe seroconversion rates were of the order of 30%with conventional and pegylated interferon alpha and approximately 20%for NUCs.HBe sero-conversion rates increase with continued NUCs treatment,but are a?ected if resistance occurs (B1).Loss of HBsAg rates after one year were 3–4%with pegylated interferon alpha,1%with lamivudine,0%with adefovir,2%with entecavir,0%with telbivudine,and 3%with tenofovir.
(2)In HBeAg-negative patients,virological response
rates at one year (undetectable HBV DNA,de?ned variously in the di?erent trials and di?erently from the present guidelines)were 63%,72%,51%,90%,88%and 91%with pegylated interferon alpha-2a,lamivudine,adefovir,entecavir,telbivudine and tenofovir,respectively (Fig.2)[41,45–49].Loss of HBsAg rates after one year were 3%with pegylated interferon alpha and 0%with lamivudine,adefovir,entecavir,telbivudine or tenofovir.4.6.Indications for treatment
The indications for treatment are generally the same for both HBeAg-positive and HBeAg-negative CHB.This is based mainly on the combination of three criteria:
Serum HBV DNA levels.
Serum aminotransferase levels. Histological grade and
stage.
European Association for the Study of the Liver /Journal of Hepatology 50(2009)227–242231
Patients should be considered for treatment when HBV DNA levels are above2000IU/ml(i.e.approxi-mately10,000copies/ml)and/or the serum ALT levels are above the upper limit of normal(ULN)for the lab-oratory,and liver biopsy(or non-invasive markers when validated in HBV-infected patients)shows moderate to severe active necroin?ammation and/or?brosis using a standardised scoring system(for example at least grade A2or stage F2by METAVIR scoring)(A1).Indications for treatment must also take into account age,health status,and availability of anti-viral agents in individual countries.
The following special groups of patients should be considered:
Immunotolerant patients:most patients under30 years of age with persistently normal ALT levels and a high HBV DNA level(usually above107IU/ ml),without any suspicion of liver disease and with-out a family history of HCC or cirrhosis do not require immediate liver biopsy or therapy.Follow-up is mandatory(B1).
Patients with mild CHB:patients with slightly ele-vated ALT(less than2times ULN)and mild histo-logical lesions(less than A2F2with METAVIR scoring)may not require therapy.Follow-up is man-datory(B1).
Patients with compensated cirrhosis and detectable HBV DNA may be considered for treatment even if ALT levels are normal and/or HBV DNA levels are below2000IU/ml(i.e.approximately10,000 copies/ml)(B1).
Patients with decompensated cirrhosis require urgent antiviral treatment.Rapid and profound viral sup-pression and e?cacious prevention of resistance are particularly needed in this group.Signi?cant clinical
improvement can be associated with control of viral replication,but patients with very advanced liver dis-ease may not always bene?t if treated at this late stage and should be considered for liver transplanta-tion(A1).
4.7.Predictors of response
Certain general baseline and on-treatment predictors of subsequent response have been identi?ed.Predictors of response for the existing antiviral therapies at various time points vary for di?erent agents.
(1)For interferon alpha-based treatment:
Pre-treatment factors predictive of HBe serocon-
version are low viral load(HBV DNA below107
IU/ml or7log10IU/ml),high serum ALT levels
(above3times ULN),and high activity scores on
liver biopsy(at least A2)[50–52](B2).
During treatment,an HBV DNA decrease to less
than20,000IU/ml at12weeks is associated with a
50%chance of HBe seroconversion in HBeAg-posi-
tive patients and with a50%chance of sustained
response in HBeAg-negative patients[53,54].
During treatment,HBeAg decrease at week24
may predict HBe seroconversion[54,55](B2).
Further studies are needed to determine the role
of HBsAg quantitation to predict sustained vir-
ological response and HBsAg loss.
HBV genotype A and B have been shown to be
associated with a better response to interferon
alpha than genotypes C and D[56].However,the
HBV genotype has a poor individual predictive
value and currently,genotype alone should not
override the choice of treatment(B2).
232European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
(2)For NUCs treatment:
Pre-treatment factors predictive of HBe serocon-
version are low viral load(HBV DNA below107
IU/ml or7log10IU/ml),high serum ALT levels
(above3times ULN),high activity scores on
liver biopsy(at least A2)[52].
During treatment with lamivudine,adefovir or
telbivudine,a virological response at24or48
weeks(undetectable HBV DNA in a real-time
PCR assay)is associated with a lower incidence
of resistance,i.e.an improved chance of main-
tained virological response,and HBe serocon-
version in HBeAg-positive patients[41,46,57]
(B1).
HBV genotype does not in?uence the response to
any NUC.
4.8.Treatment strategies:how-to-treat
The main theoretical advantages of interferon alpha (conventional or pegylated)are the absence of resistance and the potential for immune-mediated containment of HBV infection with an opportunity to obtain a sus-tained virological response o?-treatment and a chance of HBsAg loss in patients who achieve and maintain undetectable HBV DNA.Frequent side e?ects and subcutaneous injection are the main disadvantages of interferon alpha treatment.Interferon alpha is contrain-dicated in patients with decompensated HBV-related cirrhosis or autoimmune disease and in those with uncontrolled severe depression or psychosis(A1).
Entecavir and tenofovir are potent HBV inhibitors and they have a high barrier to resistance[38,58,59]. Thus they can be con?dently used as?rst-line monother-apies(A1).The role of monotherapy with entecavir or tenofovir could be modi?ed if higher rates of resistance become apparent with longer treatment duration.
Adefovir is more expensive than tenofovir,is less e?-cacious,and engenders higher rates of resistance(A1). Telbivudine is a potent inhibitor of HBV but,due to a low genetic barrier to resistance,a high incidence of resistance has been observed in patients with high base-line levels of replication and in those with detectable HBV DNA after24weeks of therapy[41](A1).Lamivu-dine is an inexpensive agent,but engenders very high rates of resistance with monotherapy[60,61](A1).
Several treatment options exist for individual patients,making rational choices for?rst-and second-line treatment sometimes di?cult.Two di?erent treat-ment strategies are applicable in both HBeAg-positive and HBeAg-negative CHB patients:treatment of?nite duration with pegylated interferon alpha or NUCs and long-term treatment with NUCs.
(1)Treatment of?nite duration with pegylated inter-
feron alpha or NUCs.This strategy is intended
to achieve a sustained virological response o?-treatment(A1).
Finite-duration treatment with pegylated
interferon alpha:a48-week course of pegylated
interferon alpha is mainly recommended for
HBeAg-positive patients with the best chance
of HBe seroconversion.It can also be used for
HBeAg-negative patients who have the best
chance of a sustained response o?-treatment.In
both groups,these are patients with high base-
line ALT(>3times ULN)and HBV DNA less
than2?106IU/ml(approximately107copies/
ml)or6.3log10IU/ml at baseline.Full informa-
tion about the advantages,adverse events and
inconveniences of pegylated interferon alpha
versus NUCs(Table2)should be provided so
the patient can participate in the decision(B2).
The combination of pegylated interferon alpha
with lamivudine showed a higher on-treatment
response but did not show a higher rate of sus-
tained response.There is limited information o-
n the e?cacy and safety of combination of
pegylated interferon alpha with other NUCs a-
nd presently this type of combination is not
recommended.
Finite-duration treatment with NUCs is achiev-
able for HBeAg-positive patients who develop
HBe seroconversion on treatment.However,
duration is unpredictable prior to therapy as it
depends on when HBe seroconversion occurs.
HBe seroconversion is more frequent in patients
with high baseline ALT(>3times ULN)and H-
BV DNA less than2?106IU/ml(approximately
107copies/ml)or6.3log10IU/ml at baseline(A1).
An attempt at?nite treatment should use the most
potent agents with the highest barrier to resistance
(entecavir or tenofovir)to rapidly reduce levels of
viremia to undetectable levels and avoid rebounds
due to HBV resistance(A1).Telbivudine might be
used in patients with good predictors of response
(HBV DNA<2?106IU/ml,i.e.approximately
107copies/ml,or6.3log10IU/ml at baseline)with
veri?cation of HBV DNA suppression below de-
tection in real-time PCR assay at24weeks.Once
HBe seroconversion occurs on NUC,treatment
should be prolonged for an additional6to
(preferentially)12months;a durable response
(persistence of anti-HBe antibodies o?-treat-
ment)can be expected in80%of these patients
(B1).
(2)Long-term treatment with NUCs.This strategy is
necessary for patients who cannot achieve a sus-tained virological response o?-treatment and require extended therapy,i.e.for HBeAg-positive patients who do not develop HBe seroconversion and in HBeAg-negative patients.This strategy is
European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
233
also recommended in patients with cirrhosis irre-
spective of HBeAg status or HBe seroconversion
on treatment(A1).
The most potent drugs with the optimal resistance pro?le,i.e.tenofovir or entecavir,should be used as ?rst-line monotherapies(A1).It is optimal to maintain HBV DNA suppression to undetectable HBV DNA in real-time PCR,whatever the drug used(B1).The long-term e?ects,safety and tolerability of entecavir and ten-ofovir(i.e.after?ve to ten years)are still unknown.
There are as yet no data to indicate an advantage of de novo combination treatment with NUCs in naive patients receiving either entecavir or tenofovir(C1). Therapeutic trials are in progress.Some experts rec-ommend a de novo combination therapy approach to prevent potential resistance in patients with a high likelihood of developing resistance(high baseline HBV DNA levels)or in whom the occurrence of viral resistance would be life-threatening due to the under-lying condition(cirrhosis).However,the long-term safety of the combination of NUCs,and in particular of the combination of entecavir and tenofovir is unknown and this approach is costly(B2).Tenofovir plus lamivudine,or tenofovir plus emtricitabine in one tablet,may be considered de novo for these patients(C1).
4.9.Treatment failure
It is important to distinguish between primary non-response(less than1log10drop of HBV DNA at12 weeks),partial virological response(detectable HBV DNA on real-time PCR assay during continuous ther-apy)and virological breakthrough due to antiviral drug resistance[29,62].
non-response.Primary
non-response to be more frequent with adefovir(approx-imately10–20%)than with other NUCs because of suboptimal dosing.A rapid switch to tenofovir or
entecavir is recommended(B1).Primary non-
response is rarely observed with lamivudine,tel-
bivudine,entecavir or tenofovir.In patients with
primary non-response,it is important to check
for compliance.In a compliant patient with a pri-
mary non-response,identi?cation of possible HBV
resistance mutations can formulate a rescue
strategy that must reasonably be based on an early
change to a more potent drug that is active against
the resistant HBV variant(B1).
Partial virological response.Partial virological
response may be encountered with all available
NUCs.It is important to check for compliance.
In patients receiving lamivudine,adefovir or tel-
bivudine with a partial virological response at
week24,two strategies can be used:change to a
more potent drug(entecavir or tenofovir)or addi-
tion of a more potent drug that does not share
cross-resistance(add tenofovir to lamivudine or
telbivudine,or add entecavir to adefovir)(A1).
In patients receiving entecavir or tenofovir with a
partial virological response at week48,some
experts would suggest adding the other drug in
order to prevent resistance in the long term(C1).
The long-term safety of tenofovir and entecavir
in combination is however unknown.
(3)Virological breakthrough.Virological break-
through in compliant patients is related to viral
resistance.Rates of resistance at up to5years of
administration are shown for the di?erent NUCs
in Fig.3.Resistance is associated with prior treat-
ment with NUCs(i.e.,lamuvidine,adefovir,tel-
bivudine,emtricitabine)or,in treatment-naive
patients,with high baseline HBV DNA levels,a
slow decline in HBV DNA and partial virological
response during treatment.Resistance should be
identi?ed as early as possible before clinical break-
through(increased ALT)by means of HBV DNA
monitoring,and if possible identi?cation of the
pattern of resistance mutations should be used to
adapt therapeutic strategies.Indeed,clinical and
virological studies have demonstrated the bene?t
of an early treatment adaptation,as soon as viral
load increases[52,63](A1).
In case of resistance,an appropriate rescue therapy should be initiated with the most e?ective antiviral e?ect and the minimal risk to induce multiple drug-resistant strains.Therefore,adding-on a second drug without cross-resistance is the only e?cient strategy.Table3 shows cross-resistance data for the most frequent resis-tant HBV variants[64].The safety of some combina-tions in the long term is unknown.
Lamivudine resistance:add tenofovir(add adefovir if tenofovir not yet available)(B1).
Table2
Main respective advantages and disadvantages of pegylated interferon
alpha and NUCs in the treatment of CHB
Pegylated interferon alpha NUCs
Advantages Finite duration Potent antiviral e?ect
Absence of resistance Good tolerance
Higher rates of HBe and
HBs seroconversion
Oral administration
Disadvantages Moderate antiviral e?ect Inde?nite duration
Poor tolerance Risk of resistance
Subcutaneous injections Lower rates of HBe
and HBs seroconversion
234European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
Adefovir resistance:it is recommended to switch to ten-
if available and add a second drug without cross-If an N236T substitution is present,add lamivudine,entecavir or telbivudine or switch to ten-ofovir plus emtricitabine (in one tablet)(C1).If an A181T/V substitution is present,add entecavir (the safety of the tenofovir–entecavir combination is unknown)or switch to tenofovir plus emtricitabine (B1).
Telbivudine resistance:add tenofovir (add adefovir if tenofovir not yet available).The long-term safety of these combinations is unknown (C1).
Entecavir resistance:Add tenofovir (the safety of this combination is unknown)(C1).
Tenofovir resistance:resistance to tenofovir has not been described so far.It is recommended that genotyp-ing and phenotyping be done by an expert laboratory to determine the cross-resistance pro?le.Entecavir,telbivudine,lamivudine or emtricitabine could be added (the safety of these combinations is unknown)(B1).
4.10.How to monitor treatment and stopping points 4.10.1.Finite therapy with pegylated interferon alpha In patients treated with pegylated interferon alpha,full blood counts and serum ALT levels should be mon-itored monthly.Serum HBV DNA level should be assessed at weeks 12and 24to verify primary response.
In HBeAg-positive patients,HBeAg and anti-HBe antibodies should be checked at weeks 24and 48and 24weeks post-treatment.HBe seroconversion together with ALT normalisation and serum HBV
DNA below 2000IU/ml (approximately 10,000copies/ml),i.e.3.3log 10IU/ml,is the desired out-come (A1).Undetectable serum HBV DNA by real-time PCR during follow-up is the optimal out-come since it is associated with a high chance of HBsAg loss.HBeAg-positive patients who develop HBe seroconversion with pegylated interferon or NUCs require long follow-up because of the possi-bility of HBe seroreversion or HBeAg-negative chronic hepatitis B.HBsAg should be checked at 6-month intervals after HBe seroconversion if HBV DNA is undetectable.Quantitative HBsAg assay is still a research tool.In case of a primary non-response,i.e.failure to achieve a 1log 10reduc-tion from baseline at 12weeks,interferon treat-ment should be stopped and replaced by a NUC (B1).
HBeAg-negative patients should be similarly moni-tored for e?cacy and safety through 48weeks of treatment.A virological response with HBV DNA <2000IU/ml (approximately 10,000copies/ml),i.e. 3.3log 10IU/ml,is generally associated with remission of the liver disease.Undetectable HBV DNA in real-time PCR is the ideal desired o?-treatment sustained response with a high probabil-ity of HBsAg loss in the longer term.HBsAg should be checked at 6-month intervals if HBV DNA is undetectable (B1).
All patients treated with pegylated interferon alpha should be monitored for the known adverse e?ects of interferon.
European Association for the Study of the Liver /Journal of Hepatology 50(2009)227–242
235
4.10.2.Finite treatment with NUCs in HBeAg-positive patients
The objective of?nite treatment with NUCs is HBe seroconversion.HBV DNA should be measured every 12weeks.HBV DNA suppression to undetectable levels in real-time PCR and subsequent HBe seroconversion is associated with biochemical and histological responses. Studies have suggested that NUC therapy can be stopped24to48weeks after HBe seroconversion(B1). HBsAg should be checked at6-month intervals after HBe seroconversion.HBsAg loss is however rarely observed after NUC therapy.
4.10.3.Long-term therapy with NUCs
HBV DNA levels should be monitored at week12to ascertain virological response and then every12to24 weeks.HBV DNA reduction to undetectable levels by real-time PCR(i.e.below10–15IU/ml)should ideally be achieved to avoid resistance.HBV DNA monitoring is thus critical to detect treatment failure(A1).In HBeAg-positive patients,HBeAg and subsequently anti-HBe antibodies once HBeAg is negative should be measured at intervals of6to12months.
NUCs are cleared by the kidneys,and appropriate dosing adjustments are recommended for patients with reduced creatinine clearance(A1).Drug concentrations are comparable in patients with varying degrees of hepatic impairment but this has not been fully studied. Exacerbations of hepatitis B may occur and require more intensive monitoring(monthly in the?rst three months)in patients with cirrhosis.The onset of compli-cations in these patients requires urgent management (B1).Renal impairment has rarely been reported in patients with HIV infection receiving anti-HBV drugs, or in patients receiving nephrotoxic drugs and treated with tenofovir or adefovir10mg/day and appropriate monitoring for nephrotoxicity and dose adjustments is necessary.
Decreases in bone mineral density have rarely been reported in HIV-positive patients treated with tenofovir (B2).Long-term study is needed.Long-term monitoring for carcinogenesis with entecavir is ongoing.Myopathy has rarely been reported in CHB patients treated with
Peripheral neuropathy has
been observed treated with pegylated interferon and telbivu-dine;this combination should be avoided(B1).
Treatment of patients with severe liver disease
4.11.1.Treatment of patients with cirrhosis
Treatment of patients with cirrhosis should not be based on ALT levels,as these may be normal in advanced disease.Interferon alpha increases the risk of sepsis and decompensation in patients with advanced cirrhosis.However,interferon can be used for the treat-ment of well compensated cirrhosis[65](A1).The use of potent NUCs with very low risk of resistance,i.e.ten-ofovir or entecavir,is particularly relevant in this group of patients(B1).Close monitoring of HBV DNA levels is important and resistance must be prevented by adding a second drug without cross-resistance if HBV DNA is not undetectable at week48of therapy.If lamivudine has to be prescribed(because of local policy),it should be used in combination with adefovir or preferably ten-ofovir(B1).
Hepatic decompensation may occur with exacerba-tions of disease that must be distinguished from non-compliance and resistance[40].Thus patients with cirrhosis require long-term therapy,with careful moni-toring for resistance and?ares.Clinical studies indicate that prolonged and adequate suppression of HBV DNA may stabilize patients and delay or even obviate need for transplantation[37,66](B1).Partial regression of?bro-sis has been reported.
4.11.2.Treatment of patients with decompensated cirrhosis
Patients with decompensated cirrhosis should be trea-ted in specialized liver units,as the application of antivi-ral therapy is complex,and these patients may be candidates for liver transplantation.End-stage liver dis-ease should be treated as a matter of urgency.Treatment is indicated even if HBV DNA level is low in order to prevent recurrent reactivation.Potent NUCs with good
Table3
Cross-resistance data for the most frequent resistant HBV variants.The amino-acid substitution pro?les are shown in the left column and the level of susceptibility is given for each drug:S(sensitive),I(intermediate/reduced susceptibility),R(resistant)[64]
HBV variant Level of susceptibility
Lamivudine Telbivudine Entecavir Adefovir Tenofovir Wild-type S S S S S
M204I R R I S S
L180M+M204V R R I S S
A181T/V I S S R S
N236T S S S R I
L180M+M204V/I±I169T±V173L±M250V R R R S S
L180M+M204V/I±T184G±S202I/G R R R S S
236European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
resistance pro?les(entecavir or tenofovir)should be used.However,there are little data for the safety of these agents in decompensated cirrhosis(B1).Patients may show slow clinical improvement over a period of 3–6months.However some patients with advanced hepatic disease with a high Child–Pugh or MELD score may have progressed beyond the point of no return,and may not bene?t,thus requiring transplantation if possi-ble[67].In that situation,treatment with NUCs will decrease the risk of HBV recurrence in the graft.
4.12.Prevention of recurrent hepatitis B after liver transplantation
Recurrent HBV infection in the transplanted liver has previously been a major problem.Pre-transplant therapy with a potent NUC with a high barrier to resistance is recommended for all HBsAg-positive patients undergoing liver transplantation for HBV-related end-stage liver disease or HCC,to achieve the lowest possible level of HBV DNA before trans-
[68–70](A1).To
date,lamivudine and/or
have
been given post-transplant in combina-
tion with hepatitis B immunoglobulin(HBIg).This regimen has reduced the risk of graft infection to less than10%.Adefovir has been successfully added for lamivudine resistance.Shorter courses and lower doses of HBIg and other forms of prophylaxis,including adefovir in combination with lamivudine and enteca-vir,are being studied.E?cacy and safety data with newer,more potent NUCs with lower rates of resis-tance,i.e.entecavir and tenofovir,have not been pub-lished but these agents should be considered,as profound suppression and low rates of resistance are advantageous(B1).Antiviral therapy for prophylaxis of recurrent hepatitis B probably requires life-long continuation of treatment(B1).
4.13.Treatment in special patient groups
4.13.1.HIV co-infected patients
HIV-positive patients with CHB are at increased risk of cirrhosis[71–76].Treatment of HIV may lead to?ares of hepatitis B due to immune restitution.The indications for therapy are the same as in HIV-negative patients, based on HBV DNA levels,serum ALT levels and histo-logical lesions[77].In agreement with recent HIV guide-lines,it is recommended that most coinfected patients be simultaneously treated for both HIV and HBV de novo [78].Tenofovir and emtricitabine(FTC)together,plus third agent active against HIV,are indicated[79] In a small number of patients,HBV may have to treated before HIV;adefovir and telbivudine,which are not proven to be active against HIV,should be https://www.360docs.net/doc/159186665.html,mivudine,entecavir and tenofovir have activity against both HIV and HBV and are contraindi-cated as single agents for hepatitis B in coinfected patients(A1).However,if these drugs with a low barrier to resistance do not reach the goal of undetectable HBV DNA,treatment of HIV infection should be envisaged.
HDV co-infected patients
co-infection with HDV is con?rmed by the
of detectable HDV RNA,immuno-histochem-ical staining for HDV antigen,or IgM anti-HDV.Inter-feron alpha(conventional or pegylated)is the only drug e?ective on HDV replication[80–85].The e?cacy of interferon alpha therapy should be assessed at24weeks by measuring HDV RNA levels.More than one year of therapy may be necessary,but is of unproven e?cacy [86](B2).A proportion of patients become HDV RNA-negative or even HBsAg-negative,with accompa-nying improvement in histology.NUC monotherapy does not appear to impact HDV replication and related disease.
4.13.3.HCV co-infected patients
HBV DNA level is often low or is undetectable and HCV is responsible for the activity of chronic hepatitis in most patients,although this is variable.Thus patients should receive pegylated interferon alpha with ribavirin as for HCV[87](B1).Sustained virological response(SVR)rates for HCV are broadly comparable with HCV monoinfected patients[88–91].There is a potential risk of HBV reactivation during or after clear-ance of HCV that must then be treated with NUCs (B1).
4.13.4.Acute severe hepatitis
More than95–99%of adults with acute HBV infec-tion will recover spontaneously and seroconvert to anti-HBs without anti-viral therapy.However,some patients with fulminant hepatitis or severe protracted subacute hepatic necrosis may bene?t from NUC treat-ment.Support for such a strategy may be found in a small number of reports with lamivudine but the e?-cacy is unproven(B1).As for chronic hepatitis,more potent drugs with a high barrier to resistance,i.e.ente-cavir or tenofovir,should be used.The duration of treatment is not established.However,continuation of anti-viral therapy for at least3months after serocon-version to anti-HBs or at least6months after HBe seroconversion without HBsAg loss is recommended (B2).Sometimes,the distinction between true acute hepatitis B and reactivation of chronic hepatitis B may be di?cult and may require liver biopsy.However, in both cases NUC treatment is the treatment of choice [92–94].
4.13.
5.Children
Chronic hepatitis B causes benign disease in most children.Only conventional interferon alpha,lamivu-
European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242237
dine and adefovir have been evaluated for safety and e?cacy comparable to adults[95–98].There are ongoing studies of other NUCs in children to better de?ne treat-ment strategies for children.
4.13.6.Healthcare workers
Healthcare workers,especially surgeons,involved in exposure-prone procedures who are HBsAg-positive with HBV DNA P2000IU/ml or 3.3log10IU/ml should be treated with a potent antiviral agent with a high barrier to resistance(i.e.entecavir or tenofovir), to reduce levels of HBV DNA ideally to undetectable and at least to<2000IU/ml before resuming expo-sure-prone procedures(B1).The long-term safety,e?-cacy,complications and economic implications of such
a policy in di?erent countries are unknown[99].
4.13.7.Pregnant women
adefovir and entecavir are
listed by the
as pregnancy category C drugs,and telbivudine and tenofovir as category B drugs.These classi?cations are based on the risk of teratogenicity in preclinical eval-uation.There is a considerable body of safety data in pregnant HIV-positive women who have received ten-ofovir and/or lamivudine or emtricitabine[100].Recent reports suggest that lamivudine therapy during the last trimester of pregnancy in pregnant HBsAg-positive women with high levels of viremia reduces the risk of intra-uterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIg and HBV vaccination[101].Tenofovir or tenofovir with emtricitabine or entecavir could be considered. Although apparently safe,these protocols require fur-ther con?rmation(B2).HBV-infected women should be monitored closely after delivery as exacerbations of chronic hepatitis B may occur[102].
4.13.8.Pre-emptive therapy before immunosuppressive therapy or chemotherapy
In HBV carriers receiving chemotherapy or immu-nosuppressive therapy,the risk of reactivation is high, particularly if rituximab is given alone or in combina-tion with steroids[103].All candidates for chemother-apy and immunosuppressive therapy should be screened for HBsAg and anti-HBc antibodies prior to initiation of treatment[104,105].Vaccination against HBV in seronegative patients is highly recommended.
HBsAg-positive candidates for chemo-and immuno-suppressive therapy should be tested for HBV DNA lev-receive pre-emptive NUC administration during
(regardless of HBV DNA levels)and for12 months after cessation of therapy.Most experience with pre-emptive treatment has been with lamivudine,which may su?ce for patients with low HBV DNA levels and a low risk of resistance[103,106–108].It is however rec-ommended that patients,especially those with a high HBV DNA level,be protected with a NUC with high antiviral potency and a high barrier to resistance,i.e. entecavir or tenofovir(A1).
HBsAg-negative patients with positive anti-HBc anti-bodies and undetectable HBV DNA in the serum who receive chemotherapy and/or immunosuppression should be followed carefully by means of ALT and HBV DNA testing and treated with NUC therapy upon con?rmation of HBV reactivation before ALT eleva-tion.NUC prophylaxis is also recommended in patients receiving bone marrow transplantation from a non-immune donor.
Recipients of anti-HBc-positive liver grafts should receive NUC prophylaxis combined with HBIg(A1). The optimal duration of combined prophylaxis is not known.
4.13.9.Dialysis and renal transplant patients
Most data in this group are available for lamivudine; the dose of lamivudine should be adapted for renal fail-ure[109](A1).There are reports of worsening of renal graft function in patients treated with adefovir.Enteca-vir may be the optimal choice of drug for patients under-going renal transplantation.Tenofovir should be used with caution in renal impairment(B1).
4.13.10.Extrahepatic disease
HBsAg-positive patients with extra-hepatic manifes-tations and active HBV replication may respond to antiviral https://www.360docs.net/doc/159186665.html,mivudine has been most widely used to date.Entecavir and tenofovir are expected to have enhanced e?cacy in this group and the indi-cations and management do not di?er from patients without extra-hepatic manifestations.Plasmapheresis can be useful in addition to NUC therapy in special cases(C2).
5.Unresolved issues and unmet needs
(1)Improve knowledge of the natural history,in par-
ticular of immunotolerant patients,with long-term
follow-up of cohorts:experimental studies to pro-
vide more de?nite prognostic information,and
biomarkers to determine prognosis and indications
for treatment.
(2)Develop and assess new therapeutic approaches,
particularly immunomodulatory therapies to
enhance loss of HBeAg and HBsAg and subse-
quent seroconversion.
(3)Assess the role of indirect markers(serum and bio-
physical)to assess the severity of liver disease and
for the follow-up of treated and untreated patients.
238European Association for the Study of the Liver/Journal of Hepatology50(2009)227–242
(4)Assess the role of HBV genotype to determine
prognosis and response to therapy and the risk
of resistance.
(5)Assess the e?cacy of di?erent durations(24weeks
to2years)and lower doses of pegylated interferon
alpha.
(6)Assess long-term e?cacy and safety and resistance
to new analogues(entecavir,telbivudine and
tenofovir).
(7)Better de?ne monitoring algorithms:timing of HBV
DNA measurement with the new generation of
NUCs with a high genetic barrier to resistance;role
of genotypic resistance assays in adapting therapy.
(8)Assess the role of combination therapy with two
NUCs to reduce resistance.
(9)Assess the e?cacy of the combination of pegylated
interferon alpha with potent NUCs(entecavir or
tenofovir)to increase HBe and HBs seroconver-
sion rates.
(10)Develop new drugs to manage multidrug resistant
HBV resistant to both lineages of current NUCs.
(11)Assess long-term impact of therapy on the preven-
tion of cirrhosis and its complications and HCC.
(12)Develop e?ective and optimum treatment for
HDV coinfection.
Con?icts of interest disclosure
–Patrick Marcellin has received research support from Hofmann-La Roche,Schering-Plough and Gilead Sciences and has acted as an advisor and lecturer for Hofmann-La Roche,Schering-Plough,Gilead Sciences,Novartis/Idenix and Bristol-Myers Squibb.–Geo?rey Dusheiko has received research support and has acted as an advisor to Hofmann-La Roche, Gilead Sciences,Novartis/Idenix,GlaxoSmithKline and Bristol-Myers Squibb.
–Fabien Zoulim has received research support from Gilead Sciences and BioMe′rieux and has acted as an advisor and/or lecturer for Gilead Sciences,Nov-artis/Idenix,Bristol-Myers Squibb,Transgene,Sie-mens Medical Solutions Diagnostics and Abbott Molecular.
–Rafael Esteban has acted as an advisor and lecturer for Schering-Plough,Gilead Sciences,Novartis/ Idenix,Bristol-Myers Squibb and GlaxoSmith Kline.
–Stefanos Hadziyannis has received research support from Hofmann-La Roche and Gilead Sciences,and has acted as an advisor or a lecturer to Hofmann-La Roche,Gilead Sciences,Novartis/Ide-nix,Bristol-Myers Squibb and GlaxoSmithKline.–Pietro Lampertico has acted as an advisor to Hof-mann-La Roche,Gilead Sciences,and is a lecturer for Hofmann-La Roche,GlaxoSmithKline,Gilead Sciences,Novartis/Idenix and Bristol-Myers Squibb.
–Michael Manns has received grant support,hono-raria and/or has served as an advisor for Hofmann-La Roche,Gilead Sciences,GlaxoSmithKline,Bris-tol-Myers Squibb and Novartis/Idenix.
–Daniel Shouval has received research support from Hofmann-La Roche,GlaxoSmithKline and Bristol-Myers Squibb and has been a lecturer for Gilead Sciences.
–Cihan Yurdaydin has acted as an advisor and lecturer for Gilead Sciences,Novartis/Idenix,Bristol-Myers Squibb and Hofmann-La Roche.
–Antonio Craxi has received research support and has acted as an advisor and a lecturer for Hofmann-La Roche,Gilead Sciences,Novartis/Idenix and Bris-tol-Myers Squibb.
–Xavier Forns has received research support from Hofmann-La Roche and has served as an advisor to Hofmann-La Roche and Novartis/Idenix.
–Darius Moradpour has received research support and has acted as an advisor for Hofmann-La Roche and Novartis/Idenix.
–Jean-Michel Pawlotsky has received research support from Gilead Sciences and has acted as an advisor for Hofmann-La Roche,Gilead Sciences,Novartis/Ide-nix,Bristol-Myers Squibb,Siemens Medical Solu-tions Diagnostics and Abbott Molecular.
–Joerg Petersen has received research support and has acted as an advisor and a lecturer for Hofmann-La Roche,Gilead Sciences,Novartis/Idenix and Bris-tol-Myers Squibb.
–Heiner Wedemeyer has received research support and has acted as an advisor and a lecturer for Hofmann-La Roche,Gilead Sciences,Novartis/Idenix and Bris-tol-Myers Squibb.
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